Up to 20% of patients requiring mechanical ventilation will suffer from difficult weaning (the need of more than 7 days of weaning after the first spontaneous breathing trial), which may depend on several reversible causes: respiratory and/or cardiac load, neuromuscular and neuropsychological factors, and metabolic and endocrine disorders. Clinical consequences (and/or often causes) of prolonged mechanical ventilation comprise features such as myopathy, neuropathy, and body composition alterations and depression, which increase the costs, morbidity and mortality of this. These difficult-to-wean patients may be managed in two type of units: respiratory intermediate-care units and specialized regional weaning centers. Two weaning protocols are normally used: progressive reduction of ventilator support (which we usually use), or progressively longer periods of spontaneous breathing trials. Physiotherapy is an important component of weaning protocols. Weaning success depends strongly on patients’ complexity and comorbidities, hospital organization and personnel expertise, availability of early physiotherapy, use of weaning protocols, patients’ autonomy and families’ preparation for home discharge with mechanical ventilation.